Specific Aims For decades, African Americans (AA) have been disproportionately affected by obesity, diabetes, hypertension, and cardiovascular disease, which contributes to major health disparities. Despite increased attention, research, and behavioral/pharmacological advancements, the wide disparity in the health of AA remains a major challenge to public health in the United States. Although a large number of factors interact in complex ways to contribute to these health disparities, genetic predisposition, high levels of stress over a lifetime, (racial discrimination and socioeconomic position) and perhaps other negative environmental experiences are undoubtedly important for AA. Additionally, the increased incidence of low birth weight among AA may be factor, since being born small for gestational age is known to predispose individuals to a variety of illnesses in their adult life, including metabolic syndrome. Any and all of these factors may contribute to dysregulation of hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) function, and thereby predispose to the previously mentioned cardiovascular and metabolic disturbances. In an ongoing study we have shown that AA men and women, compared to CA men and women, have lower circulating levels of the adrenal steroids, cortisol and dehyroepiandrosterone (DHEA), at baseline and in response to metabolic and physical stressors. AA subjects also exhibit increased sensitivity to exogenous glucocorticoids, with markedly enhanced insulin responses to a standardized meal, which may predispose them to insulin resistance. Of note, these subjects were screened and did not have any overt disease, but, in spite of this, exhibited altered functioning and detectable HPA axis abnormalities. We believe these data support the concept that aberrations in HPA axis functioning may be common in AA, and contribute to the health disparities between AA and CA. Our long-term goal is to identify psychosocial, behavioral, and physiologic factors that can be modified to reduce the burden imposed by health disparities of ethnic groups. The objective of this proposal is to evaluate how the status and functioning of the HPA axis interacts with other physiologic, psychologic, and sociologic factors in AA of varying degrees of health. We are hypothesizing that differences in HPA axis regulation in AA as a function of physiological and psychological stressors, psychosocial exposures and socioeconomic status, may partially account for the health disparities among this group. The rationale for this proposal is that sufficient data exist to implicate HPA axis dysfunction as a potential mediator of multiple health disparities in AA and possibly, other ethnic groups. Specifically we intend to: a1. Quantify the relation between HPA axis functioning and measures of health status, lifestyle behaviors, life events, and psychosocial profiles in AA men and women. HPA axis functioning will be measured using salivary cortisol and DHEA concentrations before and in response to a socially provocative film. Salivary cortisol and DHEA will also be measured in the a.m. and p.m. to determine the intactness of the circadian rhythm. Changes in these biologic measures will be evaluated with respect to: birth weight, an index of health status (lipid profiles, resting blood pressure and heart rate, body fat, waist circumference), lifestyle behaviors (sleep hygiene, physical activity, dietary patterns, drinking, and smoking), socioeconomic status (SES: education and income), psychosocial factors (perceived racism, coping style, acculturation, health locus of control, and cognitive hardiness), and life events (Beck Depression Inventory, perceived stress, stressful life events, daily hassles scale). a2. Quantify the contribution of lifestyle behaviors, life events and psychosocial profiles to insulin resistance in AA men and women. Fasting blood glucose and insulin will be measured and insulin resistance/sensitivity calculated. We will analyze insulin resistance/sensitivity against the indexes described above to estimate the proportion of variance in IR that can be explained by lifestyle behaviors, psychosocial factors, SES, and life events. a3. Determine how exogenous dehyroepiandrosterone (DHEA) supplementation affects insulin resistance, glucocorticoid sensitivity, and HPA axis reactivity in AA men and women. Serum insulin and glucose responses to a meal and baseline serum adiponectin, cortisol and DHEA concentrations will be examined in men and women under conditions of placebo and 0.5 mg of dexamethasone (DEX). ACTH, cortisol and DHEA will be examined in response to exercise. These measures will be evaluated before and after taking DHEA (100 mg/day) or Placebo for 4-wks. a4. Quantify the effects of exogenous DHEA supplementation on inflammatory markers and the relation between stress reactivity and inflammatory profiles. Baseline concentrations of CRP, IL6, IL1P, IL10, IL12, and TNF in serum will be examined under conditions of placebo and 0.5 mg of dexamethasone (DEX) and in response to exercise. Serum levels will be re-evaluated again after taking DHEA (100 mg/day) or Placebo for 4-wks. To accomplish these aims, two studies will be conducted. The first study will include up to 600 AA men and women who will provide a blood sample for fasting levels of blood glucose, insulin, and DHEAS and complete multiple questionnaires (as noted above). In addition, salivary samples will be obtained for measuring cortisol and DHEA over a 24 hours period. After the baseline sample, participants will view 30 min of a socially provocative movie, after which another salivary sample will be obtained for measuring cortisol and DHEA. Heart rate and blood pressure will be determined, along with height, weight, body fat, and waist circumference. For the second study, we will recruit a subset of participants from study one. AA men (n=40) and AA women (n=40) will undergo baseline testing to quantify glucocorticoid sensitivity (0.5 mg DEX) and establish insulin, glucose, and HPA reactivity to exercise and a meal. Participants will then take 100 mg of DHEA (or placebo) for 4 wks and then undergo the same tests. Inflammatory profiles (CRP, IL6, IL1p, IL10, IL12, and TNFa) will be quantified at baseline and after supplementation with DHEA or Placebo for 4-wks.